Dataset Information

Mechanisms Ensuring Endothelial Junction Integrity Beyond VE-Cadherin.

ABSTRACT: Endothelial junctions provide blood and lymph vessel integrity and are essential for the formation of a vascular system. They control the extravasation of solutes, leukocytes and metastatic cells from blood vessels and the uptake of fluid and leukocytes into the lymphatic vascular system. A multitude of adhesion molecules mediate and control the integrity and permeability of endothelial junctions. VE-cadherin is arguably the most important adhesion molecule for the formation of vascular structures, and the stability of their junctions. Interestingly, despite this prominence, its elimination from junctions in the adult organism has different consequences in the vasculature of different organs, both for blood and lymph vessels. In addition, even in tissues where the lack of VE-cadherin leads to strong plasma leaks from venules, the physical integrity of endothelial junctions is preserved. Obviously, other adhesion molecules can compensate for a loss of VE-cadherin and this review will discuss which other adhesive mechanisms contribute to the stability and regulation of endothelial junctions and cooperate with VE-cadherin in intact vessels. In addition to adhesion molecules, endothelial receptors will be discussed, which stimulate signaling processes that provide junction stability by modulating the actomyosin system, which reinforces tension of circumferential actin and dampens pulling forces of radial stress fibers. Finally, we will highlight most recent reports about the formation and control of the specialized button-like junctions of initial lymphatics, which represent the entry sites for fluid and cells into the lymphatic vascular system.

SUBMITTER: Duong CN

PROVIDER: S-EPMC7326147 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mechanisms Ensuring Endothelial Junction Integrity Beyond VE-Cadherin.

Duong Cao Nguyen CN Vestweber Dietmar D

Frontiers in physiology 20200521

Endothelial junctions provide blood and lymph vessel integrity and are essential for the formation of a vascular system. They control the extravasation of solutes, leukocytes and metastatic cells from blood vessels and the uptake of fluid and leukocytes into the lymphatic vascular system. A multitude of adhesion molecules mediate and control the integrity and permeability of endothelial junctions. VE-cadherin is arguably the most important adhesion molecule for the formation of vascular structur ...[more]

PMID: 32670077

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Project description:RATIONALE:The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. OBJECTIVE:We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. METHODS AND RESULTS:We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and ?-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/?-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. CONCLUSIONS:These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

Dataset Information

Mechanisms Ensuring Endothelial Junction Integrity Beyond VE-Cadherin.

Publications

Mechanisms Ensuring Endothelial Junction Integrity Beyond VE-Cadherin.

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